A small-molecule metastasis inhibitor, norcantharidin, downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells

Yu Jen Chen, Wei Min Chang, Yi Wen Liu, Chia Yun Lee, Yi Hua Jang, Cheng Deng Kuo, Hui Fen Liao

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Norcantharidin (NCTD) is a small-molecule metastasis inhibitor without renal toxicity derived from a renal toxic compound cantharidin, which is found in blister beetles (Mylabris phalerata Pall.), commonly used in traditional Chinese medicine. The anti-metastatic capacity of NCTD is apparently through the downexpression of matrix metalloproteinase-9 (MMP-9) activity. The aim of this study was to clarify the transcriptional regulation of MMP-9 gene by NCTD in colorectal cancer CT-26 cells. NCTD not only downregulated MMP-9 mRNA and protein expression, but also inhibited gelatinase activity in a concentration- and time-dependent manner. In CT26 cells with transfection of cis-element reporter plasmids, NCTD treatment decreased reporter luciferase activity from a Sp1 construct, augmented with a NF-κB construct, but this did not occur with an AP-1 construct. Further transfecting with constructs containing wild-type or various mutant MMP-9 promoters in CT26 cells indicated that Sp1, but not the others, was required for NCTD-inhibition of MMP-9 promoter transactivation. More evidence by electrophoretic mobility shift assay demonstrated that NCTD inhibited the DNA-binding activity of Sp1. In addition, the increase effect of NF-κB-luciferase activity by NCTD may include the upexpression of nuclear STAT1 and result in competitive suppression of NF-κB-binding activity in MMP-9 promoter. In conclusion, the metastasis inhibitor NCTD downregulates MMP-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer CT26 cells.

Original languageEnglish
Pages (from-to)440-446
Number of pages7
JournalChemico-Biological Interactions
Volume181
Issue number3
DOIs
Publication statusPublished - Oct 30 2009

Keywords

  • Colorectal cancer
  • Matrix metalloproteinase-9 (MMP-9)
  • Norcantharidin
  • Sp1

ASJC Scopus subject areas

  • Toxicology

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